Osteoporosis is a common disabling bone disease, particularly in post-menopausal women. Gradual loss of bone makes it porous and weak. Fracture of spine, hip and forearm frequently develop even without significant trauma.
Once the osteoporotic disease has developed, so much bone mass may already have been lost such that treatments directed at preventing further bone loss (for example, calcium supplements) would likely be of limited value. An ideal goal of therapy in patients with established osteoporosis with fracture is to provide a treatment program that will increase bone mass and restore "lost" bone. Unfortunately, most available treatment programs have failed to augment bone mass (Pak, The Menopause, Edit. J. J. Buchsbaum Springer-Verlag, 1983, pp. 35-54).
Sodium fluoride may be one agent capable of making more bone in osteoporosis. This possibility was first recognized in 1932, when Moller and Gudjonsson noted skeletal sclerosis in subject with overexposure with cryolite rich in fluoride (Acta Radiol., Vol. 13, 1932, pp. 269-294). It is now known that fluoride causes proliferation and increases the activity of osteoblasts, cells responsible for bone formation (Farley et al., Science, Vol. 222, 1983, pp. 330-332). When fluoride alone is given to patients with osteoporosis, the newly-formed bone is poorly mineralized (that is, deficient in calcium phosphate). However, when adequate calcium supplementation is provided along with fluoride, formation of mineralized bone may be stimulated (Jowsey et al., Amer. J. Med., Vol. 53, 1972, pp. 43-49). Using sodium fluoride (50-60 mg/day) with calcium supplement (800-1500 mg elemental calcium/day), formation of new bone has been shown on actual microscopic examination of biopsied bone (Briancon and Meunier, Orthop. Clin. North Amer., Vol. 12, 1998, pp. 629-648). Moreover, the rate of bone fracture was shown to be significantly reduced by treatment, compared to that of the untreated group (Riggs et al., N. Engl. J. Med., Vol. 306, 1982, pp. 446-450). Thus, there are sufficient references to suggest that long-term treatment with sodium fluoride could be effective in treating established osteoporosis.
Unfortunately, sodium fluoride has been associated with frequent adverse reactions. In several long-term trials, gastrointestinal side-effects (nausea, vomiting, diarrhea, bleeding) occurred in 16-50% of patients and rheumatic complications (painful foot and knee due to synovitis and plantar fascial syndrome) occurred in 17-32% (Table 1).
TABLE 1 ______________________________________ Side Effects of Conventional Sodium Fluoride Percentage of Side Effects Authors Patients ______________________________________ Gastrointestinal Riggs et al. (1980) 19.4 Riggs et al. (1982) 16.4 Briancon and 21.5 Meunier (1981) von Kesteren et al. 50.0 Rheumatic Riggs et al. (1980) 30.6 Riggs et al. (1982) 23.0 Briancon and 32.4 Meunier (1981) Franke et al. (1974) 17.4 ______________________________________
These complications have precluded the widespread acceptance of sodium fluoride for the treatment of osteoporosis. It should be noted that the above clinical trials were conducted with plain or acid resistant form of sodium fluoride. As will be shown in the embodiments of the present invention, rapid release of fluoride could have caused these complications. Sufficient amount of fluoride would have been released into the gastric juice to cause the formation of hydrofluoric acid, which could then have "corroded" gastric lining. Moreover, because of the rapid absorption of hydrofloric acid, a high level of fluoride in blood would have been reached to cause joint complications.
A slow-release form of sodium fluoride could potentially avert or minimize these complications. However, to the best of our knowledge, an effective slow-release form of sodium fluoride, as embodied in the present invention, has never been used for the long-term treatment of osteoporosis.
In a study published in the European Journal of Clinical Pharmacology, entitled "Pharmacokinetics of Fluoride in Man after Single and Multiple Oral Doses, conducted by Ekstrand, et al. (Europ. J. Clin. Pharmacol., 12:311 (1977)), subjects were studied with multiple dosing with rapid-release sodium fluoride tablets in four experiments, in each after a 12 hour fast, and also fifteen single dose experiments were conducted. It was shown that sodium fluoride as capsules or non-slow-release tablets may cause a rapid rise in serum fluoride, from 19 ug per liter to as high as 400 ug per liter within one hour when given orally as a single dose.
The Hasvold and Ekren reference (Eur. J. Clin. Pharmacol, 19:525 (1981)) describes the use of: (1) rapid-release sodium fluoride tablets; (2) the use of enteric coated sodium fluoride tablets which are resistant to gastric but not intestinal dissolution; and (3) the use of "sustained-release" sodium fluoride tablets of undisclosed composition. The experiments reported in the Hasvold and Ekren reference examine blood levels of fluoride for only 12 hours following but a single oral dose of a supposed sustained release sodium fluoride tablet. As shown in Tables 3 and 4 of the Hasvold and Ekren reference, administration of a sustained release sodium fluoride (SR) tablet resulted in a serum fluoride peak being reached after only two hours. Additionally, this serum fluoride peak shown in the Hasvold and Ekren reference was in fact above the upper limit of the fluoride therapeutic window (190 ng/ml or 10.0 micromolar). The Hasvold and Ekren reference describes a serum fluoride pattern after but a single treatment with a sustained release sodium fluoride tablet and would be likely to be toxic at a continued similar dosage. The in vivo serum fluoride levels resulting from the "sustained release" tablets of the Hasvold and Ekren reference are similar to those resulting from immediate release fluoride tablets insofar as the serum fluoride peak was within two hours and provided a potentially toxic level of sodium fluoride higher than the therapeutic window. The present invention describes a tablet usable in daily treatment to continually maintain serum sodium fluoride concentrations within a therapeutic window of 95 ng/ml to 190 ng/ml. The continued maintenance of serum fluoride levels within the therapeutic window is necessary, for example, for successful treatment of osteoporosis.
There is considerable evidence that a slow-release formulation of sodium fluoride would be desirable in the treatment of postmenopausal osteoporosis. As will be discussed under embodiments of the present invention, an effective slow-release sodium fluoride may obviate or alleviate gastrointestinal or rheumatic complications of rapid release preparations, maintain serum fluoride within the therapeutic window, augment spinal bone mass and inhibit fractures.
The tablet preparation of the present invention was sodium fluoride imbedded in wax matrix (carnauba wax). This continuation-in-part application includes a more clear definition of the discovery that an inclusion of a small amount of talc with the carnauba wax imparts or contributes to the sustained release characteristic, thus assuring favorable clinical effects observed in the treatment of osteoporosis.
Objects of the present invention include novel tablets, methods of making the tablets, and therapeutic uses of the tablets. The tablets of the present invention comprise sodium fluoride effective for the treatment of bone diseases such as osteoporosis. Therapeutic use of the tablets of the present invention precludes the major adverse patient reactions to fluoride normally heretofore experienced with the use of customary "rapid-release" sodium fluoride preparations. Another object is to optimize a slow-release mechanism for an oral sodium fluoride tablet, particularly useful for the oral administration of sodium fluoride.
Embodiments of the present invention confer slow-release characteristics to oral sodium fluoride preparations which permit protection against above-mentioned side effects of earlier fluoride preparations, while providing sufficient fluoride absorption to confer beneficial effect on bone. Evidence for this characteristic is provided herein and illustrated by Examples to follow.